The studies proposed are all outgrowths of recent clinical research by this group of investigators. All are linked by the fact that they are pharmacologic approaches which have as their aims better treatment for and a better understanding of the cause of psychotic disorders. They focus on acute psychotic disorders, especially affective disorders, as roughly 80 percent of our patients have such disorders. They take advantage of a Mental Health Clinical Research Center which provides access to 52 inpatient beds; personnel and systems for patient acquisition, data management, and biostatistical consultation; and support for inpatient hospitallization of subjects participating in placebo-controlled trials. The investigations run the range from the very practical to the rather speculative, but all hypotheses, even the most speculative, are supported by background work done here and elsewhere. The projects themselves are as follows: 1) There is a study which examines the relationship of blood levels of neuroleptics to clinical effects with the aim of defining subtherapeutic, therapeutic, and toxic blood levels of drug if such exist. Past studies in this area have shown contradictory results but recent studies of rigorous design have tended to show meaningful correlations between blood levels of drug and clinical effects. The proposed study is carefully designed, using a large sample of appropriate patients, fixed doses of medication, well-validated diagnostic and rating techniques, and both radioreceptor and chemical assay so that the role and effects of both parent drug and metabolites can be monitored. 2) There is a study which examines the role of acetycholine and the cholinergic nervous system in affective disorders and other psychotic disorders. The study, in double-blind placebo-controlled trials, determines whether cholinergic agents (oral physostigmine and lecithin) are effective antimanic agents, an effect for which there is preliminary evidence. It will also determine whether these cholinergic agents are specifically antimanic or more generally antipsychotic in their effects; a distinction of importance in treating and in classifying patients with psychotic disorders as well as in understanding the pathophysiology of such disorders. In addition, choline metabolism, as estimated from blood levels of choline, will be examined in patients with affective disorders as there is some evidence for abnormally high choline levels in patients with depression. 3) There is a study of the efficacy of S-adenosyl-L-methionine (SAMe) and its precursor, methionine, in depression. The use of SAMe, the major methyl donor in transmethylation reactions affecting several neurotransmitters, cell membranes, etc., may offer a unique, side-effect-free treatment of depression and a novel pharmacologic approach for studies of the biochemistry of depression.